Voltage clamp experiments were performed to evaluate and compare the effects of the anticonvulsants ethosuximide and valproate on the gating and permeability of the excitable Na and K channels of the squid giant axon. The drugs were shown to be highly specific in their effects on channel gating and ion permeability with regard to membrane side of application. Both drugs, when applied internally, affect the Na channel activation gating in ways that lead to the conclusion that they do not also act as channel blockers. However, external ethosuximide is clearly a voltage-independent Na channel blocker with no effect on channel gating. On the K channel, ethosuximide appears to have a mixed action affecting both gating and the ion flux through open channels. However, valproate slows K channel gating without effect on flux through open-gate channels. The Na channel results were confirmed by gating current measurements. The dose-response curve of the effects is similar to that of ethanol, although the anticonvulsant data are for much lower concentrations. These results suggest important implications for drug control of paroxysmal discharge and synchronous impulse generation in neural tissue. Some of the quaternary derivatives of lidocaine (QX572) produce a differential block of squid axon sodium current depending upon whether they are placed internally or externally. External QX572 produces a tonic block of INa whereas internal QX572 produces a phasic block. It is is true that local anesthetics have only a single blocking site, and that they must cross the membrane to reach that site, then the qualitative nature of the block should be independent of where they are placed. These preliminary results suggest that something different is occurring, although the exact nature of this process is still to be uncovered.